Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
G protein-coupled receptors (GPCR) are guanine nucleotide exchange factors for heterotrimeric G-proteins, whose α and βγ subunits dissociate and regulate effectors. Gαs stimulates adenylyl cyclase, and Gαi inhibits adenylyl cyclase. GPCRs are the largest receptor family (˜3% of genome) and are the largest class of attractive drug targets in disease since they are expressed on the plasma membrane and are tissue specific.
CLL is the most common form of adult leukemia in the Western world. It is characterized by the accumulation of CDS+, CD19+ and CD23+ B-cells due to decreased apoptosis. CLL shows a highly variable clinical course spanning from indolent, slow growing to aggressive, which requires immediate treatment. A clinical problem for many heterogeneous diseases, such as chronic lymphocytic leukemia, is the lack of identification of molecular and cellular markers that can predict progression. Current agents for treating CLL include classical cancer chemotherapeutic drugs (such as alkylating agents that inhibit DNA synthesis), corticosteroids, agents toxic to cells, or certain antibodies that block other types of surface antigens. However, CLL is still considered as an incurable disease for which new diagnostic tools and new therapies are needed. Since CLL patients have two types: indolent (slowly progressive) and aggressive (rapidly progressive) disease, better ways are needed to diagnose, predict and treat those patients who progress from indolent to aggressive disease.